Patient-derived Huntington's disease iPS cell models represent a substantial advance over previous cell models of HD, but they have a number of disadvantages ? a long, complex and expensive differentiation protocol, heterogeneous differentiated cell phenotypes, variability of experimental results, and difficulty in production of sufficient amounts of differentiated cells for biochemical assays or pharmacological screens. We have therefore developed a strategy to differentiate iPS cells to a striatal precursor stage, and immortalize them, to derive homogeneous clonal lines. These cells can be maintained as routine monolayer cultures and differentiated to a medium-spiny neuron phenotype in only two weeks (versus 3 months for iPSCs). We hypothesize that differentiated immortalized Striatal Precursor Neurons (SPNs) will recapitulate the CAG-repeat-expansion-associated phenotypes of the HD iPSCs, and should have advantages in being more homogenous, and more suitable for development of screenable assays to identify HD therapeutics. In the R21 phase, we will generate an allelic series of SPNs, perform omics analysis of the cell lines, and validate their suitability for screening in a 24-well plate format. In the R33 phase, we will format the assay for 96-well plates and screen with libraries of small molecules including a library of inhibitors of protein kinases for targets identified in our NINDS/CHDI supported project to study posttranslational modifications (PTMs) of huntingtin. We believe these cells will be highly amenable for development into a screenable cell model for drug discovery efforts.